In order to study the effects of nicotine on liver, groups of rats were given nicotine doses that simulated those seen in chronic smoking (54 and 108 mumol/l of nicotine) for 10 days. A subgroup was also given a single subcutaneous injection of 6 g/kg of carbon tetrachloride (CCl4) shortly before the animals of the group were killed. Histology demonstrated a significant hepatotoxic effect in the group receiving 108 mumol/l of nicotine when compared with the control group in the form of fatty change, focal or confluent necrosis and dark-cell change. The effects in pregnant rats were less severe. Carbon tetrachloride alone induced significant fatty change and focal necrosis in non-pregnant rats but not in pregnant rats. Nicotine also aggravated the CCl4 induced pathological changes in livers of both non-pregnant and pregnant animals. Thus nicotine alone, when given at a concentration of 108 mumol/l, exerted hepatotoxic effects; the alkaloid also aggravated the hepatotoxicity of CCl4. Pregnant rats were more resistant to the hepatotoxic effects produced by nicotine and CCl4.

The cellular iron uptake is a precisely controlled process to fulfill the iron demand for the synthesis and functions of a variety of iron-containing proteins, and one of the main molecules involved is the transferrin receptor (TfR), which mediates the uptake process via the transferrin cycle. The TfR expression is tightly regulated by factors such as intracellular iron level, cell proliferation or erythropoiesis at levels of receptor recycling, transcriptional or posttranscriptional control. The iron-regulatory protein/iron-responsive element system has been widely used to explain changes in receptor expression during iron loading or depletion, oxidative stress and nitric oxide stimulation. On the other hand, transcriptional control of TfR expression appears to be more important in erythroid differentiation and general cell proliferation. There is also an increasing awareness of the clinical application and experimental therapeutics based on the TfR functioning and expression. In this review, we attempt to provide a concise account of the studies of TfR structure and function as well as those areas that have not been reviewed in depth, in particular, tissue-specific regulation of TfR, the molecular mechanisms of TfR expression, and the use of TfR as diagnostic and therapeutic tools. The regulation of TfR expression in various tissues is related to its specific cellular iron requirements. Hemoglobin-synthesizing cells exhibit distinct features of iron metabolism and TfR expression as compared to most non-erythroid cells which synthesize a much lower amount of heme. For most non-erythroid cells, iron can regulate the TfR expression in a reciprocal manner through modulating the stability of the receptor mRNA whereas in hemoglobin-synthesizing cells, the TfR expression is independent of the cellular iron loading. In spite of a wide heterogeneity in the way receptor redistribution is in response to various stimuli, regulation of the constitutive expression of TfR is one of the ways of regulating the cellular iron uptake. This expression operates on both transcriptional and posttranscriptional levels. In general, factors related to cell growth and differentiation operate on the gene transcription level, whereas iron regulates the fate of the mature mRNA.

The roles of Na+/H+ antiport and intracellular pH in apoptosis of HL-60 cells were investigated here. We found that dimethyl amiloride, a specific Na+/H+ antiport inhibitor, induced intracellular acidification but not apoptosis; while sodium ionophore, monensin caused intracellular alkalinization as well as apoptosis in HL-60 cells. Br-A23187 and thapsigargin could induce a various degree of intracellular alkalinization through the stimulation of Na+/H+ antiport. Dimethyl amiloride blocked the intracellular alkalinization and inhibited apoptosis induced by Br-A23187 and thapsigargin. PMA also stimulated Na+/H+ antiport and induced intracellular alkalinization which was completely blocked by dimethyl amiloride and partially attenuated by PKC inhibitors. PMA could inhibit apoptosis in HL-60 cells. PMA-induced suppression of apoptosis was, however, not interfered by dimethyl amiloride, but could be abolished by PKC inhibitors. These results indicate that pHi alkalinization and/or the stimulation of Na+/H+ antiport, instead of intracellular acidification, are contributory to the induction of apoptosis. PMA-induced inhibition of apoptosis is not necessarily associated with intracellular alkalinization, but primarily due to activation of PKC. We suggest that stimulation of Na+/H+ antiport and pHi alkalinization act as facilitating factors in the induction of apoptosis.

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